The ergot alkaloids and their derivatives comprise a group of naturally occuring and semi-synthetic compounds which display a wide variety of pharmacological activities. Most of the ergot alkaloid compounds possess the same basic ring system, namely the tetracyclic nitrogen-containing ring system represented by the formula ##SPC1##
This ring system has been given the trivial name "ergoline, " and this name will be used throughout this specification. The term "ergoline" as used herein will include compounds of the above formula having a 9,10-double bond.
Ergot alkaloids and derivatives thereof are often classified into one of two groups; the lysergic acid amides and the clavines. The lysergic acid amides are derivatives of D-6-methyl-8-carboxy-.DELTA..sup.9 -ergoline, a 9-ergolene referred to as lysergic acid, and normally display valuable and unique pharmacologic properties, including in some cases the capacity for inducing abnormal psychic states. Compounds of the clavine class are characterized as being derivatives of D-6-methyl-8-(optionally substituted)methyl-.DELTA..sup.8 or .DELTA..sup.9 -ergolines, and most of the clavine-related compounds display useful pharmacological properties. For instance, elymoclavine is D-6-methyl-8-hydroxymethyl-8-ergolene, a .DELTA..sup.8 -ergoline, and is useful as an inhibitor of the secretion of the pituitary hormone, prolactin.
Typically, the ergot alkaloids and their derivatives possess a characteristic 2,3-unsaturation, as shown in the above general formula. Only a limited number of 2,3-dihydro-ergot alkaloid derivatives, known as 2,3-dihydroergolines, are known to date. The 2,3-unsaturation of several lysergic acid amides was reduced by Stadler et. al., as described in Helv. Chem. Acta. 47, 756(1964). Similarly, Johnson et al. converted certain amides of lysergic acid to the corresponding 2,3-dihydro, the 9,10-dihydro, and the 2,3,9,10-tetrahydro derivatives. The authors concluded that only 9,10-dihydrolysergamides possessed potent emetic activity; see J. Med. Chem., 16, 532(1973). Kharasch, in U.S. Pat. No. 2,086,559, reported the reduction of ergotocin, a lysergamide derivative, to dihydroergotocin, a useful oxytocic agent. This reduction, however, involved the 9,10-double bond rather than the 2,3-double bond.
Generally, conversion of an ergoline to the corresponding 2,3-dihydro derivative appears to diminish the pharmacological activity of the parent ergoline. It is an object of this invention to provide 2,3-dihydroergolines having equal, if not enhanced, pharmacological properties, as compared with the parent ergoline, especially the ability to inhibit prolactin secretion. The new 2,3-dihydroergolines of this invention also are useful as intermediates leading to other new ergolines.